Impaired nuclear functions in micronuclei results in genome instability and chromothripsis

Abstract

Micronuclei (MN) have generally been considered a consequence of DNA damage and, as such, have been used as markers of exposure to genotoxic agents. However, advances in DNA sequencing methods and the development of high-resolution microscopy with which to analyse chromosome dynamics in live cells have been fundamental in building a more refined view of the existing links between DNA damage and micronuclei. Here, we review recent progress indicating that defects of micronuclei affect basic nuclear functions, such as DNA repair and replication, generating massive damage in the chromatin of the MN. In addition, the physical isolation of chromosomes within MN offers an attractive mechanistic explanation for chromothripsis, a massive local DNA fragmentation that produces complex rearrangements restricted to only one or a few chromosomes. When micronuclear chromatin is reincorporated in the daughter cell nuclei, the under-replicated, damaged or rearranged micronuclear chromatin might contribute to genome instability. The traditional conception of micronuclei has been overturned, as they have evolved from passive indicators of DNA damage to active players in the formation of DNA lesions, thus unravelling previously unforeseen roles of micronuclei in the origins of chromosome instability.

The Cycle of Kinetochore-Negative Micronuclei and Chromosome Fragments Occurred in Mitosis of Hela Cells

“…If MN chromatin is reincorporated in daughter cell nuclei, the damaged MN chromatin might contribute to genome instability. Thus, MNi are not only passive indicators of DNA damage but also active players in the formation of DNA lesions and genome instability [17,18].…”

“…The MN-bearing cells frequently produced daughter cells with MNi through chromosome lagging during cell division [16]. MNi were partly reincorporated into daughter nuclei after mitosis [17]. If this is the case, there should be significant differences between cells with K …”

Inflammatory signaling in genomically instable cancers

“…As a consequence, multiple "nuclear" processes do not function properly in micronuclei. [40]. Among these disturbed processes, micronuclei show defects in nucleo-cytoplasmic transport, which impairs the recruitment of the MCM components of the replicative DNA helicase as well as DNA repair proteins [37].…”

BUBR1 Insufficiency in Mice Increases Their Sensitivity to Oxidative Stress

“…It is well-known that a genetic defect plays a role in leukemia. Micronuclei are a hallmark of DNA damage and markers of exposure to genotoxic agents (24). Using BubR1 +/− and wild-type mouse embryonic fibroblasts cells, Dai et al showed that the number of micronuclei was greatly increased in the low BUBR1 condition (5).…”

“…These double stimulations, such as chromosomal instability and genotoxicity, might accelerate the accumulation of DNA damage. Recently, one study reported that such accumulation of massive DNA damage in micronuclei may cause chromothripsis to occur (24). Chromothripsis explains massive local DNA fragmentation producing complex rearrangements restricted to only one or a few chromosomes.…”